TheraTech, Inc. is seeking to develop a novel therapy for rheumatoid arthritis (RA). The aim of the project is develop a peptide-based drug- targeting conjugate that specifically pinpoints and kills activated T- lymphocytes, cells that mediate the disease. RA is a multisystem autoimmune disease of unknown etiology. It is prevalent worldwide, affects all races and is the cause of severe morbidity and early mortality. Current therapies for patients with RA, including nonsteroidal anti-inflammatory drugs (disease-modifying anti- rheumatic drugs) have been moderately successful in reducing the comforts associated with the disease. These therapies, however, are inadequate and cause significant adverse side effects. A large body of evidence indicates that activation and infiltration of CD4+ T-lymphocytes are the primary mediators of this disease. Targeted T-lymphocyte interventions in RA have shown promising results. Treatment results with total lymphoid irradiation, cyclosporin, antithymocyte globulin, anti-CD4 and anti-lL-2R monoclonal antibodies are encouraging development of targeted T- lymphocyte approaches to RA. TheraTech proposes an attractive alternative specifically targeting activated T-lymphocytes. This therapy uses drug targeting conjugates consisting of a polymer backbone, peptide ligands as targeting moieties, and a cytotoxic drug. The peptide ligand proposed in this study has the ability to selective bind to CD4 and IL-2 receptors and internalize and release the cytotoxic drug inside the activated T-lymphocytes. The project's research design and methods include chemical synthesis of these ligands into conjugates and subsequent characterization. The conjugates will then be tested in in vitro cellular assays. After optimization of the conjugates, they will be studied in new transgenic animal models for RA, with a future object of human clinical testing. This work will introduce a number of technological innovations. The conjugation of known drugs with the targeting moieties will involve novel chemical synthesis. In addition, the specific targeting of the compounds will provide a better understanding of cellular pathogenesis of RA as well as more effective and safe therapy for the disease. PROPOSED COMMERCIAL APPLICATIONS: RA afflicts approximately 1 percent of the general population. During 1997, drug sales for treatment of this disease accounted for $500 million in the United States alone. These drugs, however, exhibit considerable toxicity and have little or no impact on the course of the disease. The availability of a new effective therapeutic agent, therefore, would present a significant commercial opportunity. Innovative strategies like the one proposed here would lead to the commercialization of a safe, effective, economic treatment for RA.